1. Field of the Invention (Technical Field)
The present invention relates to metallopeptides that bind to a target of interest and are agonists, antagonists or mixed agonist-antagonists, and more particularly to biologically active metallopeptides derived from biologically active known peptide sequences, including compounds specific for one or more melanocortin receptors and bombesin analogs.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Metallopeptides. Specific metallopeptides and methods for making and using receptor-specific metallopeptides are generally disclosed in International Patent Application Serial No. PCT/US02/04431, entitled Melanocortin Metallopeptides for Treatment of Sexual Dysfunction, filed Feb. 13, 2002; International Patent Application Serial No. PCT/US01/50075, entitled Identification of Target-Specific Folding Sites in Peptides and Proteins, filed Dec. 19, 2001; International Patent Application Serial No. PCT/US00/16396, entitled Melanocortin Metallopeptide Constructs, Combinational Libraries and Applications, filed Jun. 14, 2000; International Patent Application Serial No. PCT/US99/29743, entitled Metallopeptide Combinatorial Libraries and Applications, filed Dec. 14, 1999; U.S. Pat. No. 6,027,711 entitled Structurally Determined Metallo-Constructs and Applications, issued Feb. 22, 2000; U.S. Pat. No. 6,331,285 entitled Structurally Determined Cyclic Metallo-Constructs and Applications, issued Dec. 18, 2001; and U.S. Pat. No. 5,891,418, entitled Peptide—Metal Ion Pharmaceutical Constructs and Applications, issued Apr. 6, 1999, and the specifications thereof of each are incorporated herein by reference. In summary, the foregoing patents and applications teach metallopeptide compositions and methods of making and using metallopeptides, which metallopeptides are mimics of turn structures, bind to receptors of interest, and are agonists, antagonists, or mixed agonist-antagonists. In one simplified embodiment, an amino acid sequence provides an N3S1 ligand for a tetradentate metal ion such as rhenium (Re). The tri-peptide metal ion binding sequence can include amino acids in the L- or D-configuration, which may further have modified or unnatural side chains. The metallopeptides can include one or more amino acid residues, mimetics or other structures at either or both ends, and any terminal or capping group. Such a metallopeptide has the following general structure:

where R1 and R4 are the same or different and are independently selected from any terminal or capping group and optionally any one or more natural or unnatural L- or D-amino acid residues; R2 and R3 are the same or different and independently selected from any amino acid side chain moiety or derivative thereof; and M is a metal ion, such as Re.
Melanocortin. A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R), expressed in a wide distribution of peripheral tissues.
In general, compounds specific for MC1-R are believed to be useful for treatment of melanoma, including use as radiotherapeutic or drug delivery agent, and as diagnostic imaging agents, particularly when labeled with a diagnostic radioisotope. Compounds specific for MC3-R, MC4-R or MC5-R are believed to be useful in-regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of anorexia, as a weight gain aid, for treatment of obesity, and other treatment of other food intake and metabolism-related purposes. Compounds specific for MC3-R and MC4-R, among other melanocortin receptors, can be used as agents for treatment of sexual dysfunction, including male erectile dysfunction. Compounds specific for MC3-R and MC4-R, among other melanocortin receptors, can be used to regulate blood pressure, heart rate and other neurophysiologic parameters. Other melanocortin receptor-specific compounds, such as MCR-1 agonists, can be used as tanning agents to increase melanin production. Compounds specific for MCR-1 and MCR-3 may be useful in regulation of inflammatory processes.
There is a significant need for compounds with high specificity for discrete melanocortin receptors, as well as compounds that are either agonists or antagonists for specific melanocortin receptors. High affinity compounds for melanocortin receptors can be used to exploit varied physiological responses associated with the melanocortin receptors, either as agonists or antagonists. In addition, melanocortin receptors have an effect on the activity of various cytokines, and high affinity compounds for melanocortin receptors can be used to regulate cytokine activity.
Bombesin. There is further a need for compounds that mimic bombesin analogs. Such compounds can be used in cancer diagnosis and therapy and a variety of physiological responses associated with bombesin receptors, including neurological and CNS responses, such as stroke, ischemia, head injury, and learning, memory and attention disorders.
Peptides, particularly peptides consisting entirely or primarily of L-isomer natural amino acids, are subject to peptidase and other enzymatic degradation, and typically have a very short half-life in vivo. There is a need for constructs made of amino acids but which are not susceptible to peptidase and other enzymatic degradation, or have decreased susceptibility to such degradation. The metallopeptide constructs of this invention advantageously are not subject to degradation, or have decreased susceptibility, and in most instances are excreted intact.